Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients

Andrew J. Weickhardt, Robert C. Doebele, W. Thomas Purcell, Paul A. Bunn, Ana B. Oton, Micol S. Rothman, Margaret E. Wierman, Tony Mok, Sanjay Popat, Julie Bauman, Jorge Nieva, Silvia Novello, Sai Hong Ignatius Ou, D. Ross Camidge

Research output: Contribution to journalArticle

Abstract

BACKGROUND Crizotinib is a tyrosine kinase inhibitor active against ALK, MET, and ROS1. We previously reported that crizotinib decreases testosterone in male patients. The detailed etiology of the effect, its symptomatic significance, and the effectiveness of subsequent testosterone replacement have not been previously reported. METHODS Male cancer patients treated with crizotinib had total testosterone levels measured and results compared with non-crizotinib-treated patients. Albumin, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and/or luteinizing hormone (LH) were tracked longitudinally. A subset of patients had free testosterone levels measured and a hypogonadal screening questionnaire administered. Patients receiving subsequent testosterone supplementation were assessed for symptomatic improvement. RESULTS Mean total testosterone levels were -25% below the lower limit of normal (LLN) in 32 crizotinib-treated patients (27 of 32 patients below LLN, 84%) compared with +29% above LLN in 19 non-crizotinib-treated patients (6 of 19 below LLN, 32%), P =.0012. Levels of albumin and SHBG (which both bind testosterone) declined rapidly with crizotinib, but so did FSH, LH, and free testosterone, suggesting a centrally mediated, true hypogonadal effect. Mean free testosterone levels were -17% below LLN (19 of 25 patients below LLN, 76%). Eighty-four percent (16 of 19) with low free levels, and 79% (19/24) with low total levels had symptoms of androgen deficiency. Five of 9 patients (55%) with low testosterone given testosterone supplementation had improvement in symptoms, coincident with increases in testosterone above LLN. CONCLUSIONS Symptoms of androgen deficiency and free or total/free testosterone levels should be tracked in male patients on crizotinib with consideration of testosterone replacement as appropriate.

Original languageEnglish (US)
Pages (from-to)2383-2390
Number of pages8
JournalCancer
Volume119
Issue number13
DOIs
StatePublished - Jul 1 2013
Externally publishedYes

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Testosterone
Neoplasms
Sex Hormone-Binding Globulin
Follicle Stimulating Hormone
Luteinizing Hormone
crizotinib
Androgens
Albumins
Protein-Tyrosine Kinases

Keywords

  • ALK gene rearrangements
  • crizotinib
  • hypogonadism
  • NSCLC
  • testosterone

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Weickhardt, A. J., Doebele, R. C., Purcell, W. T., Bunn, P. A., Oton, A. B., Rothman, M. S., ... Camidge, D. R. (2013). Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients. Cancer, 119(13), 2383-2390. https://doi.org/10.1002/cncr.28089

Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients. / Weickhardt, Andrew J.; Doebele, Robert C.; Purcell, W. Thomas; Bunn, Paul A.; Oton, Ana B.; Rothman, Micol S.; Wierman, Margaret E.; Mok, Tony; Popat, Sanjay; Bauman, Julie; Nieva, Jorge; Novello, Silvia; Ou, Sai Hong Ignatius; Camidge, D. Ross.

In: Cancer, Vol. 119, No. 13, 01.07.2013, p. 2383-2390.

Research output: Contribution to journalArticle

Weickhardt, AJ, Doebele, RC, Purcell, WT, Bunn, PA, Oton, AB, Rothman, MS, Wierman, ME, Mok, T, Popat, S, Bauman, J, Nieva, J, Novello, S, Ou, SHI & Camidge, DR 2013, 'Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients', Cancer, vol. 119, no. 13, pp. 2383-2390. https://doi.org/10.1002/cncr.28089
Weickhardt AJ, Doebele RC, Purcell WT, Bunn PA, Oton AB, Rothman MS et al. Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients. Cancer. 2013 Jul 1;119(13):2383-2390. https://doi.org/10.1002/cncr.28089
Weickhardt, Andrew J. ; Doebele, Robert C. ; Purcell, W. Thomas ; Bunn, Paul A. ; Oton, Ana B. ; Rothman, Micol S. ; Wierman, Margaret E. ; Mok, Tony ; Popat, Sanjay ; Bauman, Julie ; Nieva, Jorge ; Novello, Silvia ; Ou, Sai Hong Ignatius ; Camidge, D. Ross. / Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients. In: Cancer. 2013 ; Vol. 119, No. 13. pp. 2383-2390.
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abstract = "BACKGROUND Crizotinib is a tyrosine kinase inhibitor active against ALK, MET, and ROS1. We previously reported that crizotinib decreases testosterone in male patients. The detailed etiology of the effect, its symptomatic significance, and the effectiveness of subsequent testosterone replacement have not been previously reported. METHODS Male cancer patients treated with crizotinib had total testosterone levels measured and results compared with non-crizotinib-treated patients. Albumin, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and/or luteinizing hormone (LH) were tracked longitudinally. A subset of patients had free testosterone levels measured and a hypogonadal screening questionnaire administered. Patients receiving subsequent testosterone supplementation were assessed for symptomatic improvement. RESULTS Mean total testosterone levels were -25{\%} below the lower limit of normal (LLN) in 32 crizotinib-treated patients (27 of 32 patients below LLN, 84{\%}) compared with +29{\%} above LLN in 19 non-crizotinib-treated patients (6 of 19 below LLN, 32{\%}), P =.0012. Levels of albumin and SHBG (which both bind testosterone) declined rapidly with crizotinib, but so did FSH, LH, and free testosterone, suggesting a centrally mediated, true hypogonadal effect. Mean free testosterone levels were -17{\%} below LLN (19 of 25 patients below LLN, 76{\%}). Eighty-four percent (16 of 19) with low free levels, and 79{\%} (19/24) with low total levels had symptoms of androgen deficiency. Five of 9 patients (55{\%}) with low testosterone given testosterone supplementation had improvement in symptoms, coincident with increases in testosterone above LLN. CONCLUSIONS Symptoms of androgen deficiency and free or total/free testosterone levels should be tracked in male patients on crizotinib with consideration of testosterone replacement as appropriate.",
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AU - Purcell, W. Thomas

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AU - Oton, Ana B.

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AU - Mok, Tony

AU - Popat, Sanjay

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N2 - BACKGROUND Crizotinib is a tyrosine kinase inhibitor active against ALK, MET, and ROS1. We previously reported that crizotinib decreases testosterone in male patients. The detailed etiology of the effect, its symptomatic significance, and the effectiveness of subsequent testosterone replacement have not been previously reported. METHODS Male cancer patients treated with crizotinib had total testosterone levels measured and results compared with non-crizotinib-treated patients. Albumin, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and/or luteinizing hormone (LH) were tracked longitudinally. A subset of patients had free testosterone levels measured and a hypogonadal screening questionnaire administered. Patients receiving subsequent testosterone supplementation were assessed for symptomatic improvement. RESULTS Mean total testosterone levels were -25% below the lower limit of normal (LLN) in 32 crizotinib-treated patients (27 of 32 patients below LLN, 84%) compared with +29% above LLN in 19 non-crizotinib-treated patients (6 of 19 below LLN, 32%), P =.0012. Levels of albumin and SHBG (which both bind testosterone) declined rapidly with crizotinib, but so did FSH, LH, and free testosterone, suggesting a centrally mediated, true hypogonadal effect. Mean free testosterone levels were -17% below LLN (19 of 25 patients below LLN, 76%). Eighty-four percent (16 of 19) with low free levels, and 79% (19/24) with low total levels had symptoms of androgen deficiency. Five of 9 patients (55%) with low testosterone given testosterone supplementation had improvement in symptoms, coincident with increases in testosterone above LLN. CONCLUSIONS Symptoms of androgen deficiency and free or total/free testosterone levels should be tracked in male patients on crizotinib with consideration of testosterone replacement as appropriate.

AB - BACKGROUND Crizotinib is a tyrosine kinase inhibitor active against ALK, MET, and ROS1. We previously reported that crizotinib decreases testosterone in male patients. The detailed etiology of the effect, its symptomatic significance, and the effectiveness of subsequent testosterone replacement have not been previously reported. METHODS Male cancer patients treated with crizotinib had total testosterone levels measured and results compared with non-crizotinib-treated patients. Albumin, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and/or luteinizing hormone (LH) were tracked longitudinally. A subset of patients had free testosterone levels measured and a hypogonadal screening questionnaire administered. Patients receiving subsequent testosterone supplementation were assessed for symptomatic improvement. RESULTS Mean total testosterone levels were -25% below the lower limit of normal (LLN) in 32 crizotinib-treated patients (27 of 32 patients below LLN, 84%) compared with +29% above LLN in 19 non-crizotinib-treated patients (6 of 19 below LLN, 32%), P =.0012. Levels of albumin and SHBG (which both bind testosterone) declined rapidly with crizotinib, but so did FSH, LH, and free testosterone, suggesting a centrally mediated, true hypogonadal effect. Mean free testosterone levels were -17% below LLN (19 of 25 patients below LLN, 76%). Eighty-four percent (16 of 19) with low free levels, and 79% (19/24) with low total levels had symptoms of androgen deficiency. Five of 9 patients (55%) with low testosterone given testosterone supplementation had improvement in symptoms, coincident with increases in testosterone above LLN. CONCLUSIONS Symptoms of androgen deficiency and free or total/free testosterone levels should be tracked in male patients on crizotinib with consideration of testosterone replacement as appropriate.

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